Top

Published in:

Open Access 01-12-2023 | Cytokines | Research

Role of interleukin-6 and interleukin-10 in morphological and functional changes of the blood–brain barrier in hypertriglyceridemia

Authors: Beáta Barabási, Lilla Barna, Ana Raquel Santa-Maria, András Harazin, Réka Molnár, András Kincses, Judit P. Vigh, Brigitta Dukay, Miklós Sántha, Melinda E. Tóth, Fruzsina R. Walter, Mária A. Deli, Zsófia Hoyk

Published in: Fluids and Barriers of the CNS | Issue 1/2023

Abstract

Background

Hypertriglyceridemia is closely linked to atherosclerosis related inflammatory processes and blood–brain barrier (BBB) dysfunction. Using apolipoprotein B-100 (APOB-100) transgenic mice, an animal model of chronic hypertriglyceridemia, we analyzed BBB function and morphology in vitro and ex vivo. Our objective was to determine which BBB characteristics are produced mainly by interleukin (IL)-6, an atherosclerosis promoting cytokine, and whether these actions can be antagonized by IL-10, an anti-inflammatory cytokine.

Methods

Brain endothelial and glial cell cultures and brain microvessels were isolated from wild type (WT) and APOB-100 transgenic mice and were treated with IL-6, IL-10 and their combination. First, IL-6 and IL-10 production was measured in WT and APOB-100 microvessels using qPCR. Then functional parameters of endothelial cell cultures were analyzed and immunocytochemistry for key BBB proteins was performed.

Results

IL-6 mRNA levels were higher in brain microvessels than in brain parenchyma of APOB-100 transgenic mice. Transendothelial electric resistance and P-glycoprotein activity were lower, and paracellular permeability was higher in cultured APOB-100 brain endothelial cells. These features were sensitive to both IL-6 and IL-10 treatments. A decreased P-glycoprotein immunostaining was measured in transgenic endothelial cells under control conditions and in WT cells after treating them with IL-6. This effect was antagonized by IL-10. Changes in immunostaining for tight junction proteins were observed after IL-6 exposure, which were in part antagonized by IL-10. In glial cell cultures an increase in aquaporin-4 immunolabeling in the transgenic group and an increase in microglia cell density in WT glia cultures was detected after IL-6 treatment, which was antagonized by IL-10. In isolated brain microvessels a decrease in P-glycoprotein immunolabeled area fraction was measured in APOB-100 microvessels under control conditions and in WT microvessels after every cytokine treatment. ZO-1 immunolabeling showed characteristics similar to that of P-glycoprotein. No change was seen in claudin-5 and occludin immunoreactive area fractions in microvessels. A decrease in aquaporin-4 immunoreactivity was measured in WT microvessels treated by IL-6, which was antagonized by IL-10.

Conclusion

IL-6 produced in microvessels contributes to BBB impairment observed in the APOB-100 mice. We showed that IL-10 partly antagonizes the effects of IL-6 at the BBB.

Available only for authorised users

Ross R, Harker L. Hyperlipidemia and atherosclerosis. Science. 1976;193:1094–100. https://doi.org/10.1126/science.822515.CrossRefPubMed

Schwenke DC, Carew TE. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries. Arteriosclerosis. 1989;9:908–18. https://doi.org/10.1161/01.atv.9.6.908.CrossRefPubMed

Schissel SL, Jiang X, Tweedie-Hardman J, Jeong T, Camejo EH, et al. Secretory sphingomyelinase, a product of the acid sphingomyelinase gene, can hydrolyze atherogenic lipoproteins at neutral pH. Implications for atherosclerotic lesion development. J Biol Chem. 1998;273:2738–46. https://doi.org/10.1074/jbc.273.5.2738.CrossRefPubMed

Glass CK, Witztum JL. Atherosclerosis. the road ahead. Cell. 2001;104:503–16. https://doi.org/10.1016/s0092-8674(01)00238-0.CrossRefPubMed

Seino Y, Ikeda U, Ikeda M, Yamamoto K, Misawa Y, et al. Interleukin 6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine. 1994;6:87–91. https://doi.org/10.1016/1043-4666(94)90013-2.CrossRefPubMed

Kishikawa H, Shimokama T, Watanabe T. Localization of T lymphocytes and macrophages expressing IL-1, IL-2 receptor, IL-6 and TNF in human aortic intima. Role of cell-mediated immunity in human atherogenesis. Virchows Arch A Pathol Anat Histopathol. 1993;423:433–42. https://doi.org/10.1007/BF01606532.CrossRefPubMed

Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: Moving upstream to identify novel targets for atheroprotection. Circ Res. 2016;118:145–56. https://doi.org/10.1161/CIRCRESAHA.115.306656.CrossRefPubMedPubMedCentral

Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006;86:515–81. https://doi.org/10.1152/physrev.00024.2005.CrossRefPubMed

Verma S, Nakaoke R, Dohgu S, Banks WA. Release of cytokines by brain endothelial cells: A polarized response to lipopolysaccharide. Brain Behav Immun. 2006;20:449–55. https://doi.org/10.1016/j.bbi.2005.10.005.CrossRefPubMed

10.

Jonkers IJ, Mohrschladt MF, Westendorp RG, van der Laarse A, Smelt AH. Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med. 2002;112:275–80. https://doi.org/10.1016/s0002-9343(01)01123-8.CrossRefPubMed

11.

Farkas G, Márton J, Nagy Z, Mándi Y, Takács T, et al. Experimental acute pancreatitis results in increased blood-brain barrier permeability in the rat: a potential role for tumor necrosis factor and interleukin 6. Neurosci Lett. 1998;242:147–50. https://doi.org/10.1016/s0304-3940(98)00060-3.CrossRefPubMed

12.

Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37:13–25. https://doi.org/10.1016/j.nbd.2009.07.030.CrossRefPubMed

13.

Campos-Bedolla P, Walter FR, Veszelka S, Deli MA. Role of the blood-brain barrier in the nutrition of the central nervous system. Arch Med Res. 2014;45:610–38. https://doi.org/10.1016/j.arcmed.2014.11.018.CrossRefPubMed

14.

Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178–201. https://doi.org/10.1016/j.neuron.2008.01.003.CrossRefPubMed

15.

Hartz AM, Bauer B, Fricker G, Miller DS. Rapid modulation of P-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-alpha and lipopolysaccharide. Mol Pharmacol. 2006;69:462–70. https://doi.org/10.1124/mol.105.017954.CrossRefPubMed

16.

Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133–50. https://doi.org/10.1038/nrneurol.2017.188.CrossRefPubMedPubMedCentral

17.

Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and Dysfunction of the Blood-Brain Barrier. Cell. 2015;163:1064–78. https://doi.org/10.1016/j.cell.2015.10.067.CrossRefPubMedPubMedCentral

18.

Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia. 2010;58:1094–103. https://doi.org/10.1002/glia.20990.CrossRefPubMed

19.

Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P. Brain endothelial cells and the glio-vascular complex. Cell Tissue Res. 2009;335:75–96. https://doi.org/10.1007/s00441-008-0658-9.CrossRefPubMed

20.

Banks WA, Kovac A, Morofuji Y. Neurovascular unit crosstalk: Pericytes and astrocytes modify cytokine secretion patterns of brain endothelial cells. J Cereb Blood Flow Metab. 2018;38(6):1104–18. https://doi.org/10.1177/0271678X17740793.CrossRefPubMed

21.

Erta M, Quintana A, Hidalgo J. Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci. 2012;8:1254–66. https://doi.org/10.7150/ijbs.4679.CrossRefPubMedPubMedCentral

22.

Vanlandewijck M, He L, Mäe MA, Andrae J, Ando K, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554:475–80. https://doi.org/10.1038/nature25739.CrossRefPubMed

23.

He L, Vanlandewijck M, Mäe MA, Andrae J, Ando K, et al. Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types. Sci Data. 2018;5:180160. https://doi.org/10.1038/sdata.2018.160.CrossRefPubMedPubMedCentral

24.

Database of gene expression in adult mouse brain and lung vascular and perivascular cells. http://betsholtzlab.org/VascularSingleCells/database.html. Accessed 25 Oct 2022.

25.

Burmeister AR, Marriott I. The interleukin-10 family of cytokines and their role in the CNS. Front Cell Neurosci. 2018;12:458. https://doi.org/10.3389/fncel.2018.00458.CrossRefPubMedPubMedCentral

26.

Császár E, Lénárt N, Cserép C, Környei Z, Fekete R, et al. Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions. J Exp Med. 2022;219:e20211071. https://doi.org/10.1084/jem.20211071.CrossRefPubMedPubMedCentral

27.

da Fonseca AC, Matias D, Garcia C, Amaral R, Geraldo LH, et al. The impact of microglial activation on blood-brain barrier in brain diseases. Front Cell Neurosci. 2014;8:362. https://doi.org/10.3389/fncel.2014.00362.CrossRefPubMedPubMedCentral

28.

Lobo-Silva D, Carriche GM, Castro AG, Roque S, Saraiva M. Balancing the immune response in the brain: IL-10 and its regulation. J Neuroinflammation. 2016;13:297. https://doi.org/10.1186/s12974-016-0763-8.CrossRefPubMedPubMedCentral

29.

Tóth ME, Dukay B, Hoyk Z, Sántha M. Cerebrovascular changes and neurodegeneration related to hyperlipidemia: characteristics of the human ApoB-100 transgenic mice. Curr Pharm Des. 2020;26:1486–94. https://doi.org/10.2174/1381612826666200218101818.CrossRefPubMedPubMedCentral

30.

Hoyk Z, Tóth ME, Lénárt N, Nagy D, Dukay B, et al. Cerebrovascular Pathology in Hypertriglyceridemic APOB-100 Transgenic Mice. Front Cell Neurosci. 2018;12:380. https://doi.org/10.3389/fncel.2018.00380.CrossRefPubMedPubMedCentral

31.

Bjelik A, Bereczki E, Gonda S, Juhász A, Rimanóczy A, Zana M, et al. Human apoB overexpression and a high-cholesterol diet differently modify the brain APP metabolism in the transgenic mouse model of atherosclerosis. Neurochem Int. 2006;49:393–400. https://doi.org/10.1016/j.neuint.2006.01.026.CrossRefPubMed

32.

Lénárt N, Walter FR, Bocsik A, Sántha P, Tóth ME, et al. Cultured cells of the blood-brain barrier from apolipoprotein B-100 transgenic mice: effects of oxidized low-density lipoprotein treatment. Fluids Barriers CNS. 2015;12:17. https://doi.org/10.1186/s12987-015-0013-y.CrossRefPubMedPubMedCentral

33.

Perrière N, Demeuse P, Garcia E, Regina A, Debray M, et al. Puromycin-based purification of rat brain capillary endothelial cell cultures. Effect on the expression of blood-brain barrier-specific properties. J Neurochem. 2005;93:279–89. https://doi.org/10.1111/j.1471-4159.2004.03020.x.1.CrossRefPubMed

34.

Deli MA, Abrahám CS, Kataoka Y, Niwa M. Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol. 2005;25:59–127. https://doi.org/10.1007/s10571-004-1377-8.CrossRefPubMed

35.

Veszelka S, Pásztói M, Farkas AE, Krizbai I, Ngo TK, et al. Pentosan polysulfate protects brain endothelial cells against bacterial lipopolysaccharide-induced damages. Neurochem Int. 2007;50:219–28. https://doi.org/10.1016/j.neuint.2006.08.006.CrossRefPubMed

36.

Szczepkowska A, Harazin A, Barna L, Deli MA, Skipor J. Identification of reference genes for circadian studies on brain microvessels and choroid plexus samples isolated from rats. Biomolecules. 2021;11:1227. https://doi.org/10.3390/biom11081227.CrossRefPubMedPubMedCentral

37.

Walter FR, Harazin A, Tóth AE, Veszelka S, Santa-Maria AR, et al. Blood-brain barrier dysfunction in L-ornithine induced acute pancreatitis in rats and the direct effect of L-ornithine on cultured brain endothelial cells. Fluids Barriers CNS. 2022;19:16. https://doi.org/10.1186/s12987-022-00308-0.CrossRefPubMedPubMedCentral

38.

Otsu N. A Threshold Selection Method from Gray-Level Histogram. IEEE Trans Syst Man Cybernetics. 1979;9:62–6. https://doi.org/10.1109/TSMC.1979.4310076.CrossRef

39.

Dinarello CA. Historical insights into cytokines. Eur J Immunol. 2007;37(1):S34-45. https://doi.org/10.1002/eji.200737772.CrossRefPubMedPubMedCentral

40.

Murray PJ. The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci U S A. 2005;102:8686–91. https://doi.org/10.1073/pnas.0500419102.CrossRefPubMedPubMedCentral

41.

de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, et al. The influence of cytokines on the integrity of the blood-brain barrier in vitro. J Neuroimmunol. 1996;64:37–43. https://doi.org/10.1016/0165-5728(95)00148-144.CrossRefPubMed

42.

Feldmann M, Asselin MC, Liu J, Wang S, McMahon A, et al. P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study. Lancet Neurol. 2013;12:777–85. https://doi.org/10.1016/S1474-4422(13)70109-1.CrossRefPubMed

43.

Mohamed LA, Markandaiah S, Bonanno S, Pasinelli P, Trotti D. Blood-Brain Barrier driven pharmacoresistance in amyotrophic lateral sclerosis and challenges for effective drug therapies. AAPS J. 2017;19:1600–14. https://doi.org/10.1208/s12248-017-0120-6.CrossRefPubMed

44.

Iqbal M, Ho HL, Petropoulos S, Moisiadis VG, Gibb W, et al. Pro-inflammatory cytokine regulation of P-glycoprotein in the developing blood-brain barrier. PLoS ONE. 2012;7:e43022. https://doi.org/10.1371/journal.pone.0043022.CrossRefPubMedPubMedCentral

45.

Poller B, Drewe J, Krähenbühl S, Huwyler J, Gutmann H. Regulation of BCRP (ABCG2) and P-glycoprotein (ABCB1) by cytokines in a model of the human blood-brain barrier. Cell Mol Neurobiol. 2010;30:63–70. https://doi.org/10.1007/s10571-009-9431-1.CrossRefPubMed

46.

Ono S, Hu J, Shimizu N, Imai T, Nakagawa H. Increased interleukin-6 of skin and serum in amyotrophic lateral sclerosis. J Neurol Sci. 2001;187:27–34. https://doi.org/10.1016/s0022-510x(01)00514-7.CrossRefPubMed

47.

Ehrhart J, Smith AJ, Kuzmin-Nichols N, Zesiewicz TA, Jahan I, et al. Humoral factors in ALS patients during disease progression. J Neuroinflammation. 2015;12:127. https://doi.org/10.1186/s12974-015-0350-4.CrossRefPubMedPubMedCentral

48.

Nakagawa S, Deli MA, Kawaguchi H, Shimizudani T, Shimono T, et al. A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int. 2009;54:253–63. https://doi.org/10.1016/j.neuint.2008.12.002.CrossRefPubMed

49.

Hellinger E, Veszelka S, Tóth AE, Walter F, Kittel A, et al. Comparison of brain capillary endothelial cell-based and epithelial (MDCK-MDR1, Caco-2, and VB-Caco-2) cell-based surrogate blood-brain barrier penetration models. Eur J Pharm Biopharm. 2012;82:340–51. https://doi.org/10.1016/j.ejpb.2012.07.020.CrossRefPubMed

50.

Greenwood J. Characterization of a rat retinal endothelial cell culture and the expression of P-glycoprotein in brain and retinal endothelium in vitro. J Neuroimmunol. 1992;39:123–32. https://doi.org/10.1016/0165-5728(92)90181-j.CrossRefPubMed

51.

Helms HC, Hersom M, Kuhlmann LB, Badolo L, Nielsen CU, et al. An electrically tight in vitro blood-brain barrier model displays net brain-to-blood efflux of substrates for the ABC transporters, P-gp, Bcrp and Mrp-1. AAPS J. 2014;16:1046–55. https://doi.org/10.1208/s12248-014-9628-1.CrossRefPubMedPubMedCentral

52.

Fernandez C, Buyse M, German-Fattal M, Gimenez F. Influence of the pro-inflammatory cytokines on P-glycoprotein expression and functionality. J Pharm Pharm Sci. 2004;7:359–71.PubMed

53.

Sukhai M, Yong A, Pak A, Piquette-Miller M. Decreased expression of P-glycoprotein in interleukin-1beta and interleukin-6 treated rat hepatocytes. Inflamm Res. 2001;50:362–70. https://doi.org/10.1007/PL00000257.CrossRefPubMed

54.

Günzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93:525–69. https://doi.org/10.1152/physrev.00019.2012.CrossRefPubMedPubMedCentral

55.

Rochfort KD, Collins LE, Murphy RP, Cummins PM. Downregulation of blood-brain barrier phenotype by proinflammatory cytokines involves NADPH oxidase-dependent ROS generation: consequences for interendothelial adherens and tight junctions. PLoS ONE. 2014;9:e101815. https://doi.org/10.1371/journal.pone.0101815.CrossRefPubMedPubMedCentral

56.

Camire RB, Beaulac HJ, Willis CL. Transitory loss of glia and the subsequent modulation in inflammatory cytokines/chemokines regulate paracellular claudin-5 expression in endothelial cells. J Neuroimmunol. 2015;284:57–66. https://doi.org/10.1016/j.jneuroim.2015.05.008.CrossRefPubMedPubMedCentral

57.

Lin R, Chen F, Wen S, Teng T, Pan Y, et al. Interleukin-10 attenuates impairment of the blood-brain barrier in a severe acute pancreatitis rat model. J Inflamm (Lond). 2018;15:4. https://doi.org/10.1186/s12950-018-0180-0.CrossRefPubMed

58.

Fletcher SJ, Iqbal M, Jabbari S, Stekel D, Rappoport JZ. Analysis of occludin trafficking, demonstrating continuous endocytosis, degradation, recycling and biosynthetic secretory trafficking. PLoS ONE. 2014;9:e111176. https://doi.org/10.1371/journal.pone.0111176.CrossRefPubMedPubMedCentral

59.

Wigmore SJ, Sangster K, McNally SJ, Harrison EM, Ross JA, et al. De-repression of heat shock transcription factor-1 in interleukin-6- treated hepatocytes is mediated by downregulation of glycogen synthase kinase 3beta and MAPK/ERK-1. Int J Mol Med. 2007;19:413–20. https://doi.org/10.3892/ijmm.19.3.413.CrossRefPubMed

60.

Ramirez SH, Fan S, Dykstra H, Rom S, Mercer A, et al. Inhibition of glycogen synthase kinase 3β promotes tight junction stability in brain endothelial cells by half-life extension of occludin and claudin-5. PLoS ONE. 2013;8:e55972. https://doi.org/10.1371/journal.pone.0055972.CrossRefPubMedPubMedCentral

61.

Lucero D, Islam P, Freeman LA, Jin X, Pryor M, et al. Interleukin 10 promotes macrophage uptake of HDL and LDL by stimulating fluid-phase endocytosis. Biochim Biophys Acta Mol Cell Biol Lipids. 2020;1865:158537. https://doi.org/10.1016/j.bbalip.2019.158537.CrossRefPubMed

62.

Sasson E, Anzi S, Bell B, Yakovian O, Zorsky M, et al. Nano-scale architecture of blood-brain barrier tight-junctions. Elife. 2021;10:e63253. https://doi.org/10.7554/eLife.63253.CrossRefPubMedPubMedCentral

63.

Tornavaca O, Chia M, Dufton N, Almagro LO, Conway DE, et al. ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation. J Cell Biol. 2015;208:821–38. https://doi.org/10.1083/jcb.201404140.CrossRefPubMedPubMedCentral

64.

Rochfort KD, Cummins PM. Cytokine-mediated dysregulation of zonula occludens-1 properties in human brain microvascular endothelium. Microvasc Res. 2015;100:48–53. https://doi.org/10.1016/j.mvr.2015.04.010.CrossRefPubMed

65.

Bennett J, Basivireddy J, Kollar A, Biron KE, Reickmann P, et al. Blood-brain barrier disruption and enhanced vascular permeability in the multiple sclerosis model EAE. J Neuroimmunol. 2010;229:180–91. https://doi.org/10.1016/j.jneuroim.2010.08.011.CrossRefPubMed

66.

Streit WJ, Hurley SD, McGraw TS, Semple-Rowland SL. Comparative evaluation of cytokine profiles and reactive gliosis supports a critical role for interleukin-6 in neuron-glia signaling during regeneration. J Neurosci Res. 2000;61:10–20. https://doi.org/10.1002/1097-4547(20000701)61:1%3c10::AID-JNR2%3e3.0.CO;2-E.CrossRefPubMed

67.

Recasens M, Almolda B, Pérez-Clausell J, Campbell IL, González B, et al. Chronic exposure to IL-6 induces a desensitized phenotype of the microglia. J Neuroinflammation. 2021;18:31. https://doi.org/10.1186/s12974-020-02063-1.CrossRefPubMedPubMedCentral

68.

Kloss CU, Kreutzberg GW, Raivich G. Proliferation of ramified microglia on an astrocyte monolayer: characterization of stimulatory and inhibitory cytokines. J Neurosci Res. 1997;49:248–54. https://doi.org/10.1002/(SICI)1097-4547(19970715)49:2%3c248::AID-JNR13%3e3.0.CO;2-X.CrossRefPubMed

69.

Recasens M, Shrivastava K, Almolda B, González B, Castellano B. Astrocyte-targeted IL-10 production decreases proliferation and induces a downregulation of activated microglia/macrophages after PPT. Glia. 2019;67:741–58. https://doi.org/10.1002/glia.23573.CrossRefPubMed

70.

Benveniste EN, Whitaker JN, Gibbs DA, Sparacio SM, Butler JL. Human B cell growth factor enhances proliferation and glial fibrillary acidic protein gene expression in rat astrocytes. Int Immunol. 1989;1:219–228. https://doi.org/10.1093/intimm/1.3.219. Erratum in: Int Immunol 1989;1:555. https://doi.org/10.1093/intimm/1.5.555

71.

Selmaj KW, Farooq M, Norton WT, Raine CS, Brosnan CF. Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. J Immunol. 1990;144:129–35.CrossRefPubMed

72.

Hersh J, Prah J, Winters A, Liu R, Yang SH. Modulation of astrocyte phenotype in response to T-cell interaction. J Neuroimmunol. 2021;351:577455. https://doi.org/10.1016/j.jneuroim.2020.577455.CrossRefPubMed

73.

Sugimoto N, Leu H, Inoue N, Shimizu M, Toma T, et al. The critical role of lipopolysaccharide in the upregulation of aquaporin 4 in glial cells treated with Shiga toxin. J Biomed Sci. 2015;22:78. https://doi.org/10.1186/s12929-015-0184-5.CrossRefPubMedPubMedCentral

74.

Sun L, Li M, Ma X, Feng H, Song J, et al. Inhibition of HMGB1 reduces rat spinal cord astrocytic swelling and AQP4 expression after oxygen-glucose deprivation and reoxygenation via TLR4 and NF-κB signaling in an IL-6-dependent manner. J Neuroinflammation. 2017;14:231. https://doi.org/10.1186/s12974-017-1008-1.CrossRefPubMedPubMedCentral

75.

Wolburg-Buchholz K, Mack AF, Steiner E, Pfeiffer F, Engelhardt B, et al. Loss of astrocyte polarity marks blood-brain barrier impairment during experimental autoimmune encephalomyelitis. Acta Neuropathol. 2009;118:219–33. https://doi.org/10.1007/s00401-009-0558-4.CrossRefPubMed

76.

Al Ahmad A, Taboada CB, Gassmann M, Ogunshola OO. Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult. J Cereb Blood Flow Metab. 2011;31:693–705. https://doi.org/10.1038/jcbfm.2010.148.CrossRefPubMed

77.

Kovac A, Erickson MA, Banks WA. Brain microvascular pericytes are immunoactive in culture: cytokine, chemokine, nitric oxide, and LRP-1 expression in response to lipopolysaccharide. J Neuroinflam. 2011;8:139. https://doi.org/10.1186/1742-2094-8-139.CrossRef

78.

Aniszewska A, Chłodzińska N, Bartkowska K, Winnicka MM, Turlejski K, et al. The expression of interleukin-6 and its receptor in various brain regions and their roles in exploratory behavior and stress responses. J Neuroimmunol. 2015;284:1–9. https://doi.org/10.1016/j.jneuroim.2015.05.001.CrossRefPubMed

79.

Ledeboer A, Brevé JJ, Wierinckx A, van der Jagt S, Bristow AF, et al. Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. Eur J Neurosci. 2002;16:1175–85. https://doi.org/10.1046/j.1460-9568.2002.02200.x.CrossRefPubMed

80.

Cohen SS, Min M, Cummings EE, Chen X, Sadowska GB, et al. Effects of interleukin-6 on the expression of tight junction proteins in isolated cerebral microvessels from yearling and adult sheep. NeuroImmunoModulation. 2013;20:264–73. https://doi.org/10.1159/000350470.CrossRefPubMed

81.

Hubbard JA, Szu JI, Binder DK. The role of aquaporin-4 in synaptic plasticity, memory and disease. Brain Res Bull. 2018;136:118–29. https://doi.org/10.1016/j.brainresbull.2017.02.011.CrossRefPubMed

82.

Yang J, Lunde LK, Nuntagij P, Oguchi T, Camassa LM, et al. Loss of astrocyte polarization in the tg-ArcSwe mouse model of Alzheimer’s disease. J Alzheimers Dis. 2011;27:711–22. https://doi.org/10.3233/JAD-2011-110725.CrossRefPubMed

83.

Janssens K, Slaets H, Hellings N. Immunomodulatory properties of the IL-6 cytokine family in multiple sclerosis. Ann N Y Acad Sci. 2015;1351:52–60. https://doi.org/10.1111/nyas.12821.CrossRefPubMed

84.

Driessler F, Venstrom K, Sabat R, Asadullah K, Schottelius AJ. Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50. Clin Exp Immunol. 2004;135:64–73. https://doi.org/10.1111/j.1365-2249.2004.02342.x.CrossRefPubMedPubMedCentral

85.

Fasler-Kan E, Suenderhauf C, Barteneva N, Poller B, Gygax D, et al. Cytokine signaling in the human brain capillary endothelial cell line hCMEC/D3. Brain Res. 2010;1354:15–22.CrossRefPubMed

Title: Role of interleukin-6 and interleukin-10 in morphological and functional changes of the blood–brain barrier in hypertriglyceridemia
Authors: Beáta Barabási
Lilla Barna
Ana Raquel Santa-Maria
András Harazin
Réka Molnár
András Kincses
Judit P. Vigh
Brigitta Dukay
Miklós Sántha
Melinda E. Tóth
Fruzsina R. Walter
Mária A. Deli
Zsófia Hoyk
Publication date: 01-12-2023
Publisher: BioMed Central
Keyword: Cytokines
Published in: Fluids and Barriers of the CNS / Issue 1/2023
Electronic ISSN: 2045-8118
DOI: https://doi.org/10.1186/s12987-023-00418-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Role of interleukin-6 and interleukin-10 in morphological and functional changes of the blood–brain barrier in hypertriglyceridemia

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2023

Breaking barriers: exploring mechanisms behind opening the blood–brain barrier

Relationship between brain iron dynamics and blood-brain barrier function during childhood: a quantitative magnetic resonance imaging study

The influence of upright posture on craniospinal, arteriovenous, and abdominal pressures in a chronic ovine in-vivo trial

Differential proteomic profile of lumbar and ventricular cerebrospinal fluid

Characterization of an iPSC-based barrier model for blood-brain barrier investigations using the SBAD0201 stem cell line

Glucocorticoids modify intracranial pressure in freely moving rats